ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Yujing Wang,Min Xiao,Feng Cai,Yang Li,Tianli Shi,Xiaoyan Zhou,Shuhong Tian,Denggao Huang
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene-regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia-inducing factor 1α (HIF-1α) and endothelin-1(ET-1) are related to VC. In this study, we found that the expression of ET-1 and HIF-1α was enhanced after VC, the interaction between HIF-1α and ET-1 was confirmed by CO-IP and luciferase experiments. We found that ET-1 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia-inducing factor 2α (HIF-2α) and HIF-1α have antagonistic effects on each other. HIF-1α is a pro-inflammatory cytokine, and HIF-2α can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF-2α. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF-2α/HIF-1α. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF-1α and ET-1 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF-1α and ET-1 in vascular tissues and calcified VSMC, but HIF-2α expression significantly increased. Interestingly, our study confirmed that activation of HIF-1α or inhibition of HIF-2α reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF-2α/HIF-1α dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF-2α/HIF-1α, thus providing a new idea for the application of roxadustat in VC of CKD.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
CLINICAL SCIENCE
·
2025
·
IF 7.7
Renzi Zhang,Yuhua Zhong,Qiudie Liu,Mengqi Zhang,Daoxin Wang,Sheng Li,Di Qi
Acute respiratory distress syndrome (ARDS) is an acute and severe disease with a high mortality rate. The outbreak of immune inflammation in the lung is an important pathogenic mechanism of ARDS. Notably, an imbalance in macrophage polarization is an important link in the occurrence and development of this inflammatory response. Recently, neuropeptides have been shown to regulate inflammation, but the role of neuropeptides in ARDS remains unclear. The aim of this study was to investigate the regulatory effect of calcitonin gene-related peptide (CGRP) on the inflammatory response in ARDS. We found that CGRP expression was increased in the serum of ARDS patients and in both in vitro and in vivo models of ARDS. CGRP can regulate the polarization of macrophages by targeting its receptor (receptor activity-modifying protein 1); reduce the proportion of M1 macrophages; increase the proportion of M2 macrophages; and reduce pathological injury, inflammation, oxidative stress, and apoptosis in lung tissue in LPS-induced ARDS both in vitro and in vivo . Additionally, we performed transcriptome sequencing and found that hypoxia-inducible factor-1α (HIF-1α) is involved in the above process and that CGRP can alleviate ARDS-related pathological damage, inflammation, and oxidative stress by inhibiting the HIF-1α pathway to regulate macrophage polarization balance. These results indicate that CGRP has good potential for clinical translation in the treatment of pulmonary infection in ARDS. Furthermore, this study provides new ideas for the treatment of inflammatory bursts in ARDS.
研究领域:
免疫学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 1
·e70054
·
IF 3.3
Lichao Ji,Yingjie Chai,Chenhao Tong,Yanxin Hu,Jiandong Li,Baochun Lu,Jianhua Yu
Gallbladder cancer is the most prevalent malignancy of the biliary tract and has a dismal overall survival even in the present day. The development of new drugs holds promise for improving the prognosis of this lethal disease. The possible anti-neoplastic role of morusin was investigated both in vitro and in vivo. Through cell viability and colony formation assays, we observed that morusin inhibited the proliferation of gallbladder cancer cells in vitro. Wound healing and transwell assays revealed that morusin impeded the migration and invasion of gallbladder cancer cells. Given the observed morphological changes, we examined epithelial-mesenchymal transition (EMT) markers. Subsequent investigations demonstrated that morusin treatment, both in vitro and in vivo, downregulated the expression of phospho-STAT3 (Signal transducer and activator of transcription 3) and HIF-1α (Hypoxia-inducible factor 1α) in gallbladder cancer cells. Furthermore, morusin effectively reversed EMT induced by phospho-STAT3 or HIF-1α. Morusin has a reversing effect on the EMT of gallbladder cancer cells by modulating STAT3/HIF-1α signaling.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2025
·
IF 7.3
Li Honghao,Wu Junfeng,Dai Hua,Li Jiaming,Bai Xiaoyan,Sun Yueli,Lin Jiaxin,Li Yangsi,Li Peng,Shi Lingchao,Wang Zhen,Tu Haiyan,Ke Ee
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4 , rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFR L858R -driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis. Graphical : Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung cancer cell growth.
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-14
·
IF 3.9
Tang Di,Lin Qiang,Li Pei-Wen,Wang Song,Xu Kai,Huang Yue-Sheng,Lu Qi-Ping
Chronic refractory wounds are a common, costly and recurrent complication of diabetes. Platelet-rich plasma (PRP), a new therapy for chronic wounds, is limited by a long treatment period and unstable effects. FG-4592(Roxadustat) is a new prolyl-4-hydroxylation domain(PHD) inhibitor, which can stabilize hypoxia-inducible factor-1α(HIF-1α) effectively. It is a promising drug for wound repair and needs to be demonstrated via various appropriate application scenarios. This study investigated the effects of combining FG-4592 and PRP to promote diabetic wound healing. Diabetic rats were randomly assigned to five groups: nondiabetic control, diabetic untreated, diabetic + PRP, diabetic + FG-4592, and diabetic + PRP + FG-4592. Diabetes was induced with streptozotocin (STZ). A full-thickness skin defect was created, and FG-4592 (peritoneal injection) and PRP (periwound injection) were administered alone or together. Wound healing was assessed by histological analysis (Hematoxylin-Eosin (HE) and Masson staining) and protein expression of HIF-1α, VEGF(vascular endothelial growth factor), α-SMA(α-smooth muscle actin), CoL1α1(collagen type 1 alpha 1), and SDF-1(Stromal Cell-derived Factor 1) via Western blotting and qRT-PCR(Quantitative real time polymerase chain reaction). Immunohistochemistry(IHC) and immunofluorescence(IF) were also used to evaluate CD34 (Cluster of Differentiation 34), CD31(Cluster of Differentiation 31), VEGF(vascular endothelial growth factor), SDF-1(Stromal Cell-derived Factor 1), PCNA(Proliferating Cell Nuclear Antigen), and Integrin-β1 expression. The untreated diabetic group exhibited impaired wound healing, histological damage, and reduced expression of key proteins compared to the nondiabetic control group. Both PRP and FG-4592 alone improved wound healing, reduced damage, and upregulated protein expression. However, the combination of FG-4592 and PRP showed the most significant improvement. This study suggests that FG-4592 combined with PRP accelerates diabetic wound healing by enhancing endothelial progenitor cell recruitment, neovascularization, and cell proliferation and migration via upregulation of HIF-1α and its target genes. This combination therapy may provide a novel approach for treating chronic diabetic wounds.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Jiajia Pan,Lijun Meng,Rujun Li,Zicheng Wang,Wenjie Yuan,Yucheng Li,Lin Chen,Qinhao Shen,Weili Liu,Li Zhu
Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.
研究领域:
药理学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
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IF 8.758
Xingguo Zhou,Hanghang Liu,Yanhui Zheng,Yaobao Han,Tingting Wang,Hao Zhang,Qiao Sun,Zhen Li
Radiotherapy has been extensively used to treat cancer patients because it can effectively damage most solid tumors without penetration limits. A hypoxic microenvironment in solid tumors leads to severe radioresistance and expression of hypoxic inducible factor-1 (HIF-1), which results in poor efficacy of radiotherapy alone. Herein, we report the excellent efficacy of radiotherapy achieved using a new type of yolk–shell Cu2–xSe@PtSe (CSP) nanosensitizer functionalized with the HIF-1α inhibitor acriflavine (ACF). We prepare the CSP nanosensitizer through the interfacial redox reactions between chloroplatinic acid and Cu2–xSe nanoparticles (CS) and then functionalize the nanosensitizer with ACF through their electrostatic interactions. We show that the synthesized CSP nanosensitizer can arrest the cell cycle (i.e., at the gap 2/mitosis (G2/M) phases) of tumor cells to enhance their sensitivity to X-rays and decompose endogenous H2O2 into O2 to reduce hypoxia and increase the production of reactive oxygen species, which leads to severe damage to DNA double strands and apoptosis of tumor cells. We also show that the ACF on the surface of CSP nanoparticles can effectively reduce the expression of HIF-1α. All these effects lead to a low vascular endothelial growth factor, low density of microvessels in tumor, decreased cell proliferation, and increased cell apoptosis, which synergistically and drastically enhance the efficacy of radiotherapy. This work provides insights and guidance for developing novel nanosensitizers to enhance the efficacy of radiotherapy.
研究领域:
肿瘤学
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纳米医学
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放射生物学
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2024
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IF 7.6
Jinmei Cheng,Yushun Dou,Jiaxin Li,Tingting You,Yihai Wang,Mengchuan Wang,Shengjun Shi,Chun-hui Cui,Xiaopin Duan,Jisheng Xiao
Critical limb ischemia (CLI) remains a significant clinical challenge with high morbidity and mortality. Considering the critical role of hypoxia-inducible factor 1α (HIF-1α) in hypoxic site to induce angiogenesis by regulating the expression of growth factors, we prepared a cooperative composite (P-F-HKUST-1) by mixing thermo-responsive hydrogel (PPCN) with folic acid modified copper-based MOFs (F-HKUST-1) for the hindlimb ischemia therapy. The gelation of P-F-HKUST-1 in hindlimb muscle generated a more serious ischemia environment and subsequently induced the expression of HIF-1α, while the slowly released Cu 2+ from P-F-HKUST-1 increased HIF-1α stability by inactivating the factor-inhibiting hypoxia-inducible factor 1 (FIH-1), which synergistically induced the productions of downstream growth factors and finally restored the blood perfusion rapidly. In addition, P-F-HKUST-1 hydrogel exhibited a long in vivo retention time, which endowed the sustaining action on HIF-1α to reduce the frequency of administration. The rapid blood flow recovery, together with the good biocompatibility suggested that P-F-HKUST-1 could be a potential novel combined therapy (HIF-1α stimulation and stabilization) for critical limb ischemia.
研究领域:
生物医学工程
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药学
·
组织工程
·
分子生物学
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产品关联
DOI
高影响因子
Scientific Reports
·
2014
·Vol. 4
·期 1
·1-7
·
IF 5.078
Parhira Supawadee,Zhu Guo-Yuan,Jiang Ren-Wang,Liu Liang,Bai Li-Ping,Jiang Zhi-Hong
Two stereoisomeric cardenolides, uscharin (1) and a new compound, 2′- epi -uscharin (2), were isolated from the latex of Calotropis gigantea (Asclepiadaceae). Their structures were fully elucidated based on their spectroscopic data, X-ray crystallographic data and chemical evidences. Both epimers (1 and 2) exhibited strong inhibitory effects on HIF-1 activity with different magnitudes. Compound 1 showed much more potent activity than 2 and digoxin, a well-known HIF-1 inhibitor. Discrepancy in potencies between 1 and 2 revealed the contribution of a β-configuration of 2′ hydroxyl moiety for HIF-1 inhibitory activity. This is a first report of the activity of HIF-1 inhibition of thiazoline ring-containing cardenolides.
研究领域:
植物化学
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药理学
·
肿瘤学
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DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2025
·
IF 2.5
Gao Tao,Zhang Huaisheng,Xu Yuan,He Guosong,Ma Huicong,Zheng Chuanming,Li Lei,Cheng Feng,Dou Hehe,Zhang Fulong,Zhao Heng,Qiu Zhaolei
Background Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. Objective This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. Methods A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. Results HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. Conclusion HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2024
·
IF 2.5
Ye-Fang Lu,Chuang Liu,Juan Ma,Hu-Ri Piao,Changhao Zhang,Xuejun Jin,Cheng-Hua Jin
Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole ( 18a–j ) and pyrrole ( 19a–n ) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c , 19d , and 19n (IC 50 = 8.70 – 10.44 μM) showed better HIF-1α inhibitory activity than PD (IC 50 = 13.35 μM). None of these compounds showed cytotoxicity above 100 μM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.
研究领域:
药理学
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肿瘤学
·
药物化学
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DOI
PubMed
高影响因子
Current Computer-Aided Drug Design
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2024
·
IF 1.5
Na An,Dongxing Zhang,Jile Xin,Xinyi Zhang,Zhijuan Zhang,Ligang Ma,Le Zhao,Huimin Wu,Weisheng Feng,Xiaoke Zheng
Background: Si-Ni-San (SNS) is the formula prescription of Traditional Chinese Medicine (TCM) with anti-depression properties, but its underlying mechanisms remain unclear. Objective: This study provides novel approaches for the study of Traditional Chinese Medicine (TCM) and offers new opportunities for exploring the pharmacological properties of SNS. Methods: The ingredients in SNS implicated in the treatment of depression were identified and studied using network pharmacology. SwissTargetPrediction and molecular docking were used to study the interaction of SNS ingredients and their targets. The protective effect of these ingredients and their cocktail in rat pheochromocytoma cells (PC12) exposed to corticosterone (Cor) were evaluated using the CCK-8 assay, Hoechst 33342 staining, 2',7'-dichlorodihydro fluorescein diacetate (H2DCFDA) staining, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, and in-cell Western analysis. Results: The network pharmacology study showed that the HIF-1 signaling pathway was the most crucial pathway implicated in the anti-depressive property of SNS. MAPK1 (ERK2), MAPK3 (ERK1), AKT1, VEGFA, STAT3, and EGF were identified as hub target proteins in the HIF-1 signaling pathway. Quercetin, naringenin, licochalcone A, and kaempferol from SNS, which targeted the six proteins mentioned above, were used to create a cocktail. This cocktail exerted protective properties, decreased the oxidative stress in PC12 exposed to Cor, and successfully regulated the expressions of AKT1, p-AKT1, ERK1, ERK2, p-ERK1/2, STAT3, p- STAT3, and VEGFA induced by Cor exposure. The SwissTargetPrediction and molecular docking study showed that the cocktail may regulate the HIF-1 signaling pathway by directly binding with AKT1 and MAPK1. Conclusion: The cocktail from SNS comprised of quercetin, naringenin, licochalcone A, and kaempferol exerts anti-depression potentiality by modulating the HIF-1 signaling pathway via direct interactions with AKT1 and MAPK1.
研究领域:
神经药理学
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传统中药研究
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分子生物学
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药效学
·
细胞信号传导
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DOI
PubMed
高影响因子
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